Tuesday, May 14, 2013

Scientific Authority and the Role of Small RNAs

A few weeks ago I criticized Philip Ball for an article he published in Nature: DNA: Nature Celebrates Ignorance. Phil has responded to my comments and he has given me permission to quote from his response. I think this is going to stimulate discussion on some very interesting topics.

The role of small RNAs is one of those topics. There are four types of RNA inside cells: tRNA, ribosomal RNA (rRNA), messenger RNA (mRNA), and a broad category that I call “small RNAs.”

The small RNAs include those required for splicing and those involved in catalyzing specific reactions. Many of them play a role in regulating genes expression. These roles have been known for at least three decades so there haven’t been any conceptual advances in the big picture for at least that long.

What’s new is an emphasis on the abundance and importance of small regulatory RNAs. Some workers believe that the human genomes contains thousands of genes for small RNAs that play an important role in regulating gene expression. That’s a main theme for those interpreting the ENCODE results. Several prominent scientists have written extensively about the importance of this “new information” on the abundance of small RNAs and how it assigns function to most of our genome.

One of these prominent scientists is John Mattick who recently received an award from the Human Genome Organization for ....

The Award Reviewing Committee commented that Professor Mattick’s “work on long non-coding RNA has dramatically changed our concept of 95% of our genome”, and that he has been a “true visionary in his field; he has demonstrated an extraordinary degree of perseverance and ingenuity in gradually proving his hypothesis over the course of 18 years.”

Here’s the problem: who do you believe? Who are the scientific authorities on this topic?

Phil Ball writes.

To make a start, I know of course that RNA regulation is an old subject – I mentioned Cech and Altman in my 1994 book Designing the Molecular World. But it does seem that the extent and complexity of involvement of non-coding RNAs in genetics has become argued only much more recently. Certainly, I’m not aware that anyone was saying things such as “RNA is the computational engine of the system” when Cech and Altman got their Nobels. One can agree or disagree with such claims of Mattick and others, of course, but they are being prominently made – I’m not just making this up.

How are science writers supposed to know that the claims of Mattick and others are—to say the least—controversial when Mattick gets a prestigious award for "proving his hypothesis" in spite of opposition from those who want to preserve the old view of junk DNA?

Who are the authorities and how do you recognize them?1 How do science writers even know there’s a controversy if there’s nothing in the scientific literature that refutes Mattick?

1. This is an important part of my course on scientific controversies. The answer is that you should always be skeptical of claims made in the scientific literature; especially claims that a paradigm has been overthrown. You don't have to decide which authority is correct but you do have to be careful not to get bamboozled by hype.

11 comments
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The proof is in the pudding, and although I find the whole concept of lncRNAs and the like pretty cool, I've yet to be convinced that they're a general rule and not an exception. I think that the stochastic expression of most small "junk" RNAs (and often at vanishingly small levels, too) argues against their playing a major role. I could be wrong, of course (and I don't personally work on small non-coding RNAs), but the idea that all sequences in the genome can be transcribed *sometimes* does not strike me as revolutionary; it's even exactly what should be expected of a transposon-riddled genome.

I'm sure that several non-coding transcripts do indeed have a function (the role of many miRNAs seems pretty clear, and the original p21 lncRNA paper had me convinced, although a colleague of mine struggles to reproduce its results) but I'm not ready to shout "change of paradigm" just yet.

As for whom to believe, the answer is the same as usual: trust no one. Let's look at the data. And if it's not clear enough to decide, let's wait for more data.

This is particularly interesting because the plant is a specialist in nutrient-poor habitats. This might give a fitness advantage to junkless plants, though the authors say there was no sign of selection, so I am guessing you will suspect it was an accident. It would be interesting to test other carnivorous plants to see if they all have unusually small genomes....LJ

Bladderwort genomes sizes range a lot between the different species, so the selection-due-to-poor-nutrients hypothesis does not appear to broadly explain the variation. There is even some indication of population-level variation in size, but I could not find the primary reference. There is some indication of an inverse correlation with mutation rate.

ex. Greilhuber et al. Plant Biol (Stuttg). 2006 Nov;8(6):770-7.

AbstractNuclear holoploid genome sizes (C-values) have been estimated to vary about 800-fold in angiosperms, with the smallest established 1C-value of 157 Mbp recorded in Arabidopsis thaliana. In the highly specialized carnivorous family Lentibulariaceae now three taxa have been found that exhibit significantly lower values: Genlisea margaretae with 63 Mbp, G. aurea with 64 Mbp, and Utricularia gibba with 88 Mbp. The smallest mitotic anaphase chromatids in G. aurea have 2.1 Mbp and are thus of bacterial size (NB: E. coli has ca. 4 Mbp). Several Utricularia species range somewhat lower than A. thaliana or are similar in genome size. The highest 1C-value known from species of Lentibulariaceae was found in Genlisea hispidula with 1510 Mbp, and results in about 24-fold variation for Genlisea and the Lentibulariaceae. Taking into account these new measurements, genome size variation in angiosperms is now almost 2000-fold. Genlisea and Utricularia are plants with terminal positions in the phylogeny of the eudicots, so that the findings are relevant for the understanding of genome miniaturization. Moreover, the Genlisea-Utricularia clade exhibits one of the highest mutational rates in several genomic regions in angiosperms, what may be linked to specialized patterns of genome evolution. Ultrasmall genomes have not been found in Pinguicula, which is the sister group of the Genlisea-Utricularia clade, and which does not show accelerated mutational rates. C-values in Pinguicula varied only 1.7-fold from 487 to 829 Mbp.

A related discussion on Mike Taylor's blog:http://svpow.com/2013/05/03/peer-review-does-not-mean-we-can-trust-a-published-paper/See especially this comment by Mike:http://svpow.com/2013/05/03/peer-review-does-not-mean-we-can-trust-a-published-paper/#comment-32847

Jim thanks for the extra information. Interesting that Pinguicula does not have an ultrasmall genome, but Genlisea does. I wonder if anyone looked at other carnivorous plants like Nepenthes or especially Dionaea? It looks like no one has looked at Drosera (sundew) for this, but that Drosera does have some weird features (no centromeres!) and some species seem to have small chromosomes.

I could not find Nepenthes or Dionaea in the C-value databases. But it is a very interesting group to look into. If we hurry up, they will probably provide for a lot of good hypothesis testing, before everyone else measures the C-values and ruins it with post-hoc explanations ;-)

Pick the bladderwort with the biggest genome-- let's say Genlisea hispidula with 1510 Mbp [about one-half the size of the human genome].

Now do an ENCODE-type experiment with that, totting up all its biochemical "activities" as Ewan Birney would say-- find all its low-abundance RNA transcripts, everywhere a protein binds to the DNA, everywhere the DNA is chemically modified.

Who is willing to bet that the fraction of "biochemical activity" in Genlisea hispidula will be close to, or more than, the 80% "activity" reported by ENCODE for human beings?

And since Utricularia gibba with its 88 Mbp is so closely related to Genlisea, nature has already done for us the experiment of asking, "Hey, what would happen if you delete all that junk?"

Laurence A. Moran

Larry Moran is a Professor in the Department of Biochemistry at the University of Toronto. You can contact him by looking up his email address on the University of Toronto website.

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Quotations

The old argument of design in nature, as given by Paley, which formerly seemed to me to be so conclusive, fails, now that the law of natural selection has been discovered. We can no longer argue that, for instance, the beautiful hinge of a bivalve shell must have been made by an intelligent being, like the hinge of a door by man. There seems to be no more design in the variability of organic beings and in the action of natural selection, than in the course which the wind blows.Charles Darwin (c1880)Although I am fully convinced of the truth of the views given in this volume, I by no means expect to convince experienced naturalists whose minds are stocked with a multitude of facts all viewed, during a long course of years, from a point of view directly opposite to mine. It is so easy to hide our ignorance under such expressions as "plan of creation," "unity of design," etc., and to think that we give an explanation when we only restate a fact. Any one whose disposition leads him to attach more weight to unexplained difficulties than to the explanation of a certain number of facts will certainly reject the theory.

Charles Darwin (1859)Science reveals where religion conceals. Where religion purports to explain, it actually resorts to tautology. To assert that "God did it" is no more than an admission of ignorance dressed deceitfully as an explanation...

Quotations

The world is not inhabited exclusively by fools, and when a subject arouses intense interest, as this one has, something other than semantics is usually at stake.
Stephen Jay Gould (1982)
I have championed contingency, and will continue to do so, because its large realm and legitimate claims have been so poorly attended by evolutionary scientists who cannot discern the beat of this different drummer while their brains and ears remain tuned to only the sounds of general theory.
Stephen Jay Gould (2002) p.1339
The essence of Darwinism lies in its claim that natural selection creates the fit. Variation is ubiquitous and random in direction. It supplies raw material only. Natural selection directs the course of evolutionary change.
Stephen Jay Gould (1977)
Rudyard Kipling asked how the leopard got its spots, the rhino its wrinkled skin. He called his answers "just-so stories." When evolutionists try to explain form and behavior, they also tell just-so stories—and the agent is natural selection. Virtuosity in invention replaces testability as the criterion for acceptance.
Stephen Jay Gould (1980)
Since 'change of gene frequencies in populations' is the 'official' definition of evolution, randomness has transgressed Darwin's border and asserted itself as an agent of evolutionary change.
Stephen Jay Gould (1983) p.335
The first commandment for all versions of NOMA might be summarized by stating: "Thou shalt not mix the magisteria by claiming that God directly ordains important events in the history of nature by special interference knowable only through revelation and not accessible to science." In common parlance, we refer to such special interference as "miracle"—operationally defined as a unique and temporary suspension of natural law to reorder the facts of nature by divine fiat.
Stephen Jay Gould (1999) p.84

Quotations

My own view is that conclusions about the evolution of human behavior should be based on research at least as rigorous as that used in studying nonhuman animals. And if you read the animal behavior journals, you'll see that this requirement sets the bar pretty high, so that many assertions about evolutionary psychology sink without a trace.

Jerry Coyne
Why Evolution Is TrueI once made the remark that two things disappeared in 1990: one was communism, the other was biochemistry and that only one of them should be allowed to come back.

Sydney Brenner
TIBS Dec. 2000
It is naïve to think that if a species' environment changes the species must adapt or else become extinct.... Just as a changed environment need not set in motion selection for new adaptations, new adaptations may evolve in an unchanging environment if new mutations arise that are superior to any pre-existing variations

Douglas Futuyma
One of the most frightening things in the Western world, and in this country in particular, is the number of people who believe in things that are scientifically false. If someone tells me that the earth is less than 10,000 years old, in my opinion he should see a psychiatrist.

Francis Crick
There will be no difficulty in computers being adapted to biology. There will be luddites. But they will be buried.

Sydney Brenner
An atheist before Darwin could have said, following Hume: 'I have no explanation for complex biological design. All I know is that God isn't a good explanation, so we must wait and hope that somebody comes up with a better one.' I can't help feeling that such a position, though logically sound, would have left one feeling pretty unsatisfied, and that although atheism might have been logically tenable before Darwin, Darwin made it possible to be an intellectually fulfilled atheist

Richard Dawkins
Another curious aspect of the theory of evolution is that everybody thinks he understand it. I mean philosophers, social scientists, and so on. While in fact very few people understand it, actually as it stands, even as it stood when Darwin expressed it, and even less as we now may be able to understand it in biology.

Jacques Monod
The false view of evolution as a process of global optimizing has been applied literally by engineers who, taken in by a mistaken metaphor, have attempted to find globally optimal solutions to design problems by writing programs that model evolution by natural selection.